This is a request for continuation of a Research Scientist Award. My broadest objectives are to understand why people take psychoactive drugs, what are usual and expected effects, what might account for unexpected consequences and how might adverse consequences best be managed. For example, how might tolerance and dependence determine individual differences in drug use and drug effects? Individual projects study the pharmacokinetics and pharmacodynamics of cocaine and methamphetamine administered by various routes, and interactions with other drugs; for example, ethanol, caffeine and nicotine. Characteristics of tolerance and dependence associated with repeated dose subchronic cocaine administration and the utility of that experimental paradigm to evaluate new treatment medications will be studied. In other drug kinetic studies, the appearance of drug and drug metabolites in hair, saliva and sweat is being investigated to better understand and model drug disposition and to assess the utility of those media to characterize individual patterns of drug use and drug kinetics. Characterization of the pharmacokinetics and dynamics of buprenorphine and its metabolites and factors altering such effects is studied as part of the evaluation of pharmacologic treatments for opiate, cocaine and related dependence. Whenever possible, equal attention is given to psychological and behavioral measures, assessment of mood, neurophysiological and neurochemical indices. In the clinical studies, emphasis is on understanding relationships between behavioral, physiological and pharmacologic variables. Biochemical, physiologic, neuroendocrinologic, behavioral and psychometric technique are used to assess consequences of acute and subchronic drug administration. Recognizing that people rarely limit drug taking to a single drug or class of drugs, development and application of research strategies appropriate to the study of multiple classes of drugs rather than specialization with a particular methodology or drug class is a guiding philosophy. Where possible, mechanisms and explanations for individual differences in drug effects are studied. Relationships between naturally occurring and drug- induced disorders (for example, depression, anxiety states, and schizophrenia or other psychosis) remain a topic of interest. The studies are multidisciplinary and involve only human subjects. They should further understanding of human psychoactive drug use and its health consequences and management.